We have initiated a project to broaden the available fund of knowledge related to the effects of hydroxyurea (HU) of fetal hemoglobin synthesis in patients with sickle cell anemia by studying the acute and chronic responses associated with its administration to such individuals. These studies should provide insight into the pharmokinetics of HU, optimal dosage regimens, and predictive factors associated with the F-reticulocyte response. Preliminary results on 6 patients suggest that the F- reticulocyte count and fetal hemoglobin levels can be universally increased following HU administration, although the magnitude of the response is a complex function of the rate of F-cell production, enrichment and preferential survival. We are now examining the DNA haplotype around the gamma-delta-beta genes of these patients in order to look for genetic predictive factors of the F-cell response. In addition, we plan to enumerate the sequential molecular, cellular and physiological consequences resulting from HU treatment. Should a significant sustained F- cell response be observed in select patients while on HU, it may be possible to increase further the magnitude of the response by simultaneously administering short courses of cloned human erythropoietin or cloned granuloctye-macrophage colony stimulating factor. In this fashion, one may approach fetal hemoglobin levels consonant with those observed in the benign HbetaS-HPFH phenotypes.